Besremi trial

[wateron]

Two New Trials Testing Ropeginterferon (Besremi) in PV and ETMar 3, 2023John Mascarenhas, MDAssociate Professor & Director of the Adult Leukemia Program0 seconds of 8 minutes, 40 secondsDESCRIPTIONTRANSCRIPTDr. Mascarenhas: Hi, I'm John Mascarenhas, a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City. My specialty is hematology oncology. My focus is in myeloid malignancies with a research focus in myeloproliferative neoplasms.Graphic: What is ropeginterferon?Dr. Mascarenhas: So, Ropeginterferon is a type of interferon alfa-2b. It's a pegylated form, which means that it is a drug that can last longer in your body, so it's dosed less frequently, once every two weeks. And it's a drug that is approved for patients with polycythemia vera, whether you live in the European Union or the United States, and is under phase 3 testing globally for patients with higher risk essential thrombocythemia that have been previously treated with hydroxyurea.This is a drug that's considered a biologic. It's not a chemotherapeutic, and it's not a small molecule inhibitor that's taken by mouth. It's a subcutaneous injection given every two weeks and dose escalated to a target dose in order to (A) control blood counts; (B) reduce the risk of thrombosis and hemorrhage, – so clotting and bleeding – and; (C) in some patients, probably about 25% of patients, one can achieve a molecular remission, which is thought to change the natural history in the potential for progressive disease.Graphic: How does the drug work to control disease in ET and PV?Dr. Mascarenhas: So, interferon's an interesting drug. It's been around a long time, and I would argue that we don't fully understand how the drug actually works. But there are some aspects of the biology of the disease that lend itself to interferon alfa therapy. The drug's been shown to selectively turn on and delete or kill malignant stem cells over normal stem cells. And a lot of laboratory and clinical studies have documented that one can deplete and reduce the population of malignant stem cells. These are the primordial cells in the bone marrow and in the blood that give rise to the abnormal clone of blood cells in PV and ET. And interferon can, I would say quite uniquely, through various biologic mechanisms, reduce that stem cell population. Thereby, as a surrogate reducing the driver mutation level, whether you're JAK2 mutated, calreticulin mutated, or MPL mutated, and that is thought to change the burden of disease, the potential for complications and, over time, the potential for progressive disease.Graphic: What is the Exceed in ET and who would be good candidate?Dr. Mascarenhas: The Exceed trial is an open-label, early-phase clinical trial of Ropeginterferon alfa-2b, or Besremi, in patients with essential thrombocythemia that are high risk, that are either treatment-naive or been previously treated with hydroxyurea or anagrelide, but not interferon. And it will enroll patients over a number of different institutions, with a primary endpoint of achieving a hematologic response over a 12-month period. Patients who do achieve a response are then able to roll over into an extension phase trial that will allow them to continue receiving ropeginterferon alfa indefinitely to maintain that response.Graphic: What is the Eclipse in PV and who would be good candidate?Dr. Mascarenhas: The Eclipse trial in PV is a study of ropeginterferon alfa-2b in patients with polycythemia vera that are in need of treatment. And the point of the trial is really to evaluate a more aggressive dosing schema starting at 250 micrograms, going to 350 micrograms at the next dose in two weeks, and then at a target of 500 micrograms by the third dose. So within a month, you're at the target dose. It's a much faster dose escalation. We believe that, based on data that we have from the PROUD-PV and the CONTINUATION-PV studies, that dosing in this way will be well tolerated and will lead to a quicker time to complete hematologic response. So therefore, for patients in which... particularly when we are interested in attaining a hematologic response at a faster interval with more aggressive dosing, this trial, which will accrue across multiple centers, will provide us with both safety, tolerability, and efficacy readout on this approach.Graphic: What are the side effects and how are they managed?Dr. Mascarenhas: Ropeginterferon, like other interferons, is a drug that can be associated with injection-site reactions in a minority of patients or flu-like symptoms, usually the following day. These are often not severe symptoms. And for many of my patients, Tylenol or Tylenol PM and dosing at night, will usually overcome these kinds of symptoms. But some patients can feel these flu-like malaise symptoms the following day. Some patients will complain of fatigue that can last longer. Autoimmune complications have been well described with any interferon. These are, thankfully, infrequent, but need to be monitored. So, anything with an “-itis” – like hepatitis, dermatitis, thyroiditis – can be complications of interferon. We try to avoid interferon in patients that have a predisposition to autoimmune disease. So patients who have uncontrolled hypothyroidism or uncontrolled hepatitis, patients who have poorly controlled rheumatologic diseases, would not be perhaps appropriate patients for interferon alfa.The other toxicity that is important to be aware of, and needs to be monitored, and is not objective, one can't really measure it with laboratory or physical exam skills, is the neuropsychiatric complications that can occur in some patients with interferon alfa dosing. This can be mood lability, depression, anxiety, difficulty concentrating. That's why I'm very keen on making sure patients are aware of this potential toxicity, and that they and their loved ones can monitor for the onset of any symptoms of this nature. And sometimes this will require dose reductions or, in some cases, even the addition of an antidepressant or an anxiolytic, depending on the clinical case. And that has to really be determined on a case-by-case basis.And then lastly, and obviously, counts have to be monitored. The goal, at least the initial goal with interferon alfa to be is a hematologic remission. So you want to see normalization of the white count, hematocrit and platelet count. And in PV patients, the absence of phlebotomies. But with a careful monitoring, you want to avoid the potential for cytopenias or low blood counts, whether it's leukopenia (low white count), anemia (low hemoglobin), or thrombocytopenia (low platelet count). So, ropeginterferon or any type of interferon, these are similar concerns and similar strategies to try to mitigate these and monitor patients closely.Graphic: Can this drug improve outcomes for patients?Dr. Mascarenhas: I'm eager to see trials with interferon continue to evolve and explore either different dosing schemas or different patient populations. We are a site that's participating in the SURPASS study, that's the registration phase 3 study of ropeginterferon alfa-2b versus anagrelide in ET patients who've been previously treated with hydroxyurea. And that's an important study as it's a global study that will likely lead to the approval of this drug in the EU and the US for our ET patients, who frequently get the drug off-label when able. And sometimes it's not possible, so this will extend the ability to provide interferon for ET patients.I'm also participating in leading the Eclipse study, which is our PV study with the more aggressive dosing schema in order to achieve a more rapid complete hematologic remission in PV patients. And I'm eager to see the outcomes. I'm also interested to see how the Exceed study plays out because all of these studies will ultimately enhance our understanding and comfort level of dosing ropeginterferon across different populations with different dosing schemas. And that should improve our ability to care for our patients with both ET and PV.

[Elizka]

Can you share the link?

[wateron in reply to Elizka]

patientpower.info/myeloprol...

[monarch5000]

I personally wouldn't want to enroll in either of those trials. They won't tell us things we didn't already know about interferon-alfa. They are just trials intended to secure additional FDA approvals for one brand of interferon alfa - Besremi - the super expensive brand.

The trials could even be harmful to ET and PV patients in the long run because if super expensive Besremi ($13,000 a month) gains FDA approval, it will steal market share away from Pegasys interferon, ($4,000 a month) which is not FDA approved to treat MPN's, and could potentially cause the maker of Pegasys to stop production. And then patients who can tolerate Pegasys, but not Besremi, would be out of luck. As well as the patients who need interferon, but cannot afford Besremi.

Lastly, interferon works best to slow or reverse disease progression when patients start taking it before their blood counts and symptoms are bad. But if only super expensive Besremi is available, doctors and insurers will be discourage patients from starting it until blood counts and symptoms are substantially bad. Starting late would result in more patients to progressing to myelofibrosis.

[kristinmarie in reply to monarch5000]

I see your point, valid and very kind-hearted. This super expensive drug is absolutely a rip-off, and unfortunately in this world, we may have to deal with greedy people who only care about money.

That company is trying to switch the current regimens of slowly increasing the dosage to a more aggressive regimen of 250/350/500mcg. Why had they not studied this dosage variation before applying for approval?